An i-Motif-gated DNA-based nanoassembly enables pH-responsive biofilm control and enamel remineralization for initial caries therapy

Dental caries is a biofilm-mediated disease characterized by acidogenic microbial dysbiosis and enamel demineralization. Current antibacterial and remineralization strategies are often limited by poor penetration into cariogenic biofilms, nonselective antimicrobial activity, and the acid instability of mineral precursors. Here, we developed an i-Motif-gated DNA-based nanoassembly that integrates biofilm penetration, pH-responsive biofilm control, and biomimetic enamel regeneration for initial caries therapy. The nanoassembly was constructed by co-assembling i-Motif-forming DNA strands, DNA-templated silver nanoclusters and amorphous calcium phosphate precursors. In a validated three-species streptococcal biofilm model, the nanoassembly exhibited efficient penetration throughout the biofilm matrix. Under acidic cariogenic conditions, folding of the i-Motif structure promoted the release of silver-containing species, resulting in enhanced antibacterial activity against cariogenic-state biofilms while exerting minimal effects under relatively non-cariogenic conditions. Simultaneously, protonation of the DNA scaffold stabilized the amorphous calcium phosphate against acid dissolution down to pH 4.0, facilitating the regeneration of densely packed enamel-like crystals. In a rat caries model, topical treatment effectively suppressed cariogenic bacterial colonization and minimized lesion development without disrupting oral microbial diversity. These findings demonstrate that programmable DNA nanoassemblies can couple pH-responsive antibacterial activation with biomimetic mineralization, providing a promising strategy for precise management of initial caries.